This application aims to identify novel gene variants conferring susceptibility to suicidal behavior. While suicidality is perhaps the most dreaded aspect of psychiatric disorders, and among the leading causes of death among young people in the United States, relatively little research has been devoted to its biological basis. Yet family, twin, and adoption studies make clear that suicidal behavior has a substantial heritable component. While there is evidence that this heritability is accounted for in part by a liability to mood disorder, other evidence suggests an independent heritable facet that may cut across multiple psychiatric disorders. This independent feature has been hypothesized to be a liability to aggressiveness and impulsivity; the genetic study of this feature has focused on serotonergic genes because of neurobiological findings in suicidal subjects implicating this neurotransmitter. However, little systematic genetic investigation of the suicidality phenotype has been undertaken. Only in the last six years have the first attempts been made to examine the whole genome for linkage with this phenotype. The first two published studies of this kind, one using alcoholism pedigrees and the other using major depression pedigrees, both found evidence of linkage to the 2p11-12 region. Remarkably, when we examined the suicidal behavior phenotype in our bipolar disorder pedigree set, we found that the strongest evidence for linkage across the genome was in the same region, at the same markers implicated previously. This impressive confluence of findings across three genome-wide studies using differing sample types strongly suggests the presence of a gene predisposing to suicidal behavior in the 2p11- 12 region. We tested this hypothesis directly in a genome-wide association study by comparing genotypes from subjects with bipolar disorder and a history of attempted suicide (attempters) to those from subjects with bipolar disorder and no history of attempted suicide (non-attempters). This analysis identified the LRRTM4 gene, which encodes a nervous system transmembrane protein that triggers formation of excitatory synapses and localizes to 2p12. An independent case-control association study using the attempted suicide phenotype also identified the LRRTM4 gene. We propose to follow-up these results by conducting a large-scale resequencing effort designed to identify a catalog of risk alleles for LRRTM4, with the goal of identifying genetic variation that increases the risk of suicidal behavior, thereby providing unprecedented insight into the genetic basis of the phenotype. Our project will make use of the diverse and complementary skill sets of an outstanding team of investigators that includes experts in molecular genetics, statistical genetics, bioinformatics, and psychopathology. Finding genetic variants that influence suicidal behavior would allow for the identification of people with high-risk alleles and the identification of medications that influence suicidal behavior in individuals with these high-risk alleles. It would also provide new insights into the biological basis of suicidal behavior and provide new therapeutic targets.